With noncompaction there is a spectrum of expression: the condition may affect the entire mid- and apical ventricle or merely a portion of the apicolateral wall in less affected individuals purchase avanafil online now how to cure erectile dysfunction at young age, and the severity of trabeculation may vary buy genuine avanafil erectile dysfunction ugly wife. Because of this variable expression and rising awareness of this entity order avanafil master card erectile dysfunction shake recipe, definitive imaging and clinical criteria continue to be refined. In general, a ratio of trabeculated/compacted layer thickness of greater than 2, as measured on 44 short-axis views at the mid- and apical levels, is considered to be consistent with noncompaction. A more specific echocardiographic criterion may be a maximal systolic compacta thickness of less than 8 mm (in the segment with the most prominent recesses), which appears to better discriminate 45 noncompaction from normal patients and those with pressure overload hypertrophy. Segmental wall motion abnormalities, including thinning and aneurysms, may be present and are caused by fibrofatty infiltration. Echocardiography alone is insufficiently sensitive or specific for the diagnosis of arrhythmogenic cardiomyopathy, and other causes of right-sided heart dilation and arrhythmia need to be excluded. Restrictive Cardiomyopathies Systemic diseases that can infiltrate the heart may lead to restrictive cardiomyopathies (see Chapter 77); the most common is amyloidosis. Advanced diastolic dysfunction is manifested both by Doppler indices and by worsening longitudinal strain measured by speckle tracking. Amyloidosis in particular has a characteristic regional pattern of severely 47 reduced longitudinal strain at the base of the left ventricle, but relatively preserved apical strain. Apart from amyloid heart disease, echocardiography is frequently used to screen for cardiac 48 involvement by other infiltrative diseases. It may reveal abnormalities ranging from dilated to restrictive phenotypes, but no specific pattern is pathognomonic of any single cause. A restrictive filling pattern may occur earlier than the manifestations of systolic heart failure. All these parameters of function have been shown to improve with iron removal therapy. Fabry disease is associated with accumulation of glycosphingolipid in the heart and a high incidence of cardiovascular signs and symptoms in addition to renal, dermatologic, and neurologic abnormalities. More than 80% of individuals with Fabry disease will display concentric hypertrophy, although concentric remodeling and asymmetric hypertrophy occur in a smaller proportion. Endomyocardial fibrosis, also termed Löffler endocarditis, is a rare restrictive cardiomyopathy frequently accompanied by peripheral eosinophilia, which may be idiopathic or associated with helminthic infection in the tropics. Eosinophilic endocarditis and infiltration of the myocardium lead to changes that can be striking on echocardiography. The ventricular cavities themselves are small with restrictive physiology because of the fibrotic process. Patients may display retracted and incompetent atrioventricular valves and marked biatrial enlargement. Because most patients are identified relatively late in the disease, the time course of development of these changes is unclear. Heart Failure Echocardiography is key in the diagnosis and management of patients with heart failure (see Chapters 25 and 26). Echocardiography can help distinguish among the different types and narrow down the potential causes of heart failure from the main categories discussed earlier. The ability of echocardiography to predict which patients will or will not benefit remains to be proved. However, in this cautionary background, speckle tracking has emerged over the past decade as the most broadly used technique for measuring strain (tissue deformation) and dyssynchrony, in large part because it appears to be more angle- and operator-independent, robust, and reliable than prior techniques (see eFig. Data using this technique are accumulating, but standardization is needed among vendors and researchers. Assessment After Orthotopic Heart Transplantation Echocardiography is used both to certify that cardiac structure and function are normal in potential heart 53 donors and to monitor for rejection in cardiac transplant recipients (see Chapter 28). In patients who have undergone the standard Shumway-Lower technique of transplantation, the resultant atria are very enlarged and deformed because of the retained upper portion of the dilated native heart. In these patients the anastomosis between the donor and recipient heart may be visible as a thickened ridge of plicated tissue that encircles the atria. There is a trend toward newer surgical methods that either retain no recipient myocardium (i. A “normal” transplanted heart often has slight paradoxical septal motion—anterior motion of the septum in systole and a slight decrease in septal systolic thickening—that persists in the postoperative state. Cardiac allograft dysfunction may result from acute rejection, coronary artery vasculopathy, myocardial fibrosis, acute myocarditis from opportunistic infections, or tachycardia-mediated cardiomyopathy. Cardiac ultrasound may detect the “downstream” effects of these pathologic mechanisms. For now the gold standard for detecting acute rejection remains endomyocardial biopsy, although echocardiography has an appropriate supplementary role in monitoring for rejection and other complications after transplantation. Among noninvasive imaging techniques, echocardiography is the most widely investigated and used. Here we address the principles for the more widely used HeartMate devices, which are now continuous-flow pumps. The aortic valve in a completely decompressed heart stays completely closed throughout the cardiac cycle. This is ideally assessed with both M-mode and 2D imaging of the aortic valve over multiple beats. Such abnormalities may be demonstrated by 2D echocardiography or by increased velocities and turbulence seen with Doppler evaluation at the cannula/graft orifices. Lung Ultrasound in Heart Failure Lung ultrasound is a technique that can provide semiquantitative assessment of lung fluid in patients with heart failure. B-lines are vertical echogenic reverberation artifacts that arise from the pleural line and extend raylike with respirophasic movement and are markers of increased extravascular lung water (eFig. B-lines are most frequently seen in pulmonary edema but also in other processes such as acute respiratory distress syndrome and pulmonary fibrosis. B-lines are relatively sensitive and specific for cardiogenic dyspnea in the emergency department setting, and the simplicity and availability of the technique makes it attractive for early diagnosis and monitoring of therapy, particularly in limited- 56 resource environments. For studies, typically the number of B-lines are summed from two to eight segments of the chest using a 1. Stress Echocardiography Stress echocardiography is a well-validated tool for the evaluation of ischemia. The accuracy of stress echocardiography is similar to that of stress radionuclide perfusion imaging (see Chapter 16). As with other tests, stress echocardiography is best used for diagnosis or to identify the extent, severity, and location of ischemia in patients with an intermediate pretest probability of disease. In the standard stress protocol, baseline images are obtained at rest, before the patient exercises on either a treadmill or stationary bicycle. If a stationary (upright or supine) bicycle is used, the workload is increased by 25 W every 2 or 3 minutes, and echocardiographic images can be obtained on the cycle precisely at the time of peak stress. Patients who cannot exercise can undergo pharmacologic stress with a graded dobutamine infusion of up to 40 µg/kg/min (and added atropine, if necessary, to achieve the target heart rate), which increases the heart rate and myocardial contractility.

The subsequent expanded use of these imaging 21 modalities in surveillance studies revealed an incidence of approximately 7% to 10% cost of avanafil erectile dysfunction quality of life. Numerous studies have also shown resolution of these imaging abnormalities with anticoagulation discount avanafil 200mg on-line erectile dysfunction pills in malaysia, indicating valve 22 thrombosis as the etiology (Fig cheap 200 mg avanafil overnight delivery erectile dysfunction treatment nyc. Randomized studies to 5 years and single-center experience up to 10 years have not yet shown a major reason for concern regarding 9,23 durability. However, all the studies are subject to survivorship bias, and with small numbers of patients alive at 5 years or longer after the procedure, the ultimate issue of durability with surgical valves remains undetermined. Right, Calcification of the aortic root, annulus, and left ventricular outflow tract. The members of the heart team include interventional cardiologists, cardiac surgeons, imaging specialists, anesthesiologists, midlevel providers, research coordinators, fellows-in-training, and geriatricians. Recent concerns are that the heart team is logistically unwieldly and has somewhat outlived its usefulness because patient decision making has become more 25 straightforward. Clinical trials of the novel oral anticoagulants rivaroxaban and apixaban, alone and in combination with antiplatelet regimens, are ongoing. The high cost of the device, approximately $32,000, has raised questions about the ultimate cost-effectiveness of the procedure. However, some evidence shows that the decreased utilization of resources, including a shorter hospital stay, now 1 to 2 27 days in major programs, offsets the higher device costs. In the latter case, mitral valve replacement may be a better option for symptomatic relief. Inoue first used a self-positioning latex balloon wrapped with a nylon mesh to allow phased balloon expansion in 1982 and described the technique in 1984 (see Classic References). The double- balloon technique involves two peripheral arterial balloons tracked over separate guidewires placed in the left ventricle and simultaneously inflated. Following transseptal catheterization and therapeutic anticoagulation, a balloon-tipped end-hole catheter is used to traverse the mitral valve via the transseptal puncture site. A second guidewire is placed using a similar technique or by using a dual-lumen catheter. Two 18- or 20-mm dilation balloons are tracked and positioned on the wires and inflated simultaneously to dilate the valve. As such, it is important to evaluate carefully for severe commissural calcium preprocedurally. B, Association between echocardiographic score and postprocedural event-free survival. Rationale for Transcatheter Therapy Surgery improves survival in observational studies but is associated with mortality rates of 1% to 5% and additional morbidity rates of 10% to 20%, including stroke, reoperation, renal failure, and prolonged 32 ventilation. In one study of more than 30,000 patients undergoing mitral valve replacement, 33 mortality increased from 4. The risks and morbidity of surgery coupled with patient preference have stimulated attempts to develop less invasive solutions. When considering percutaneous or transcatheter approaches for mitral repair, it is useful to classify 35 them according to the major structural abnormality that they address. This system replicates the Alfieri stitch operation, in which the middle scallops of the posterior and anterior leaflets (P2 and A2, respectively) are sutured together to create a double-orifice mitral valve. The operation, although usually performed with adjunctive ring annuloplasty, has proved effective and durable 37 in a wide variety of pathologies as well as in select patients without annuloplasty. D, Side view, and E, left atrial view, of the clip delivery system as it is advanced through the mitral valve in the open position prior to grasping of the leaflets. F, The final result is illustrated after the clip has been released and the delivery system removed. The procedure is performed with standard catheterization techniques 39 using a transseptal approach from the right femoral vein. A properly aligned and oriented clip can grasp the P2 and A2 segments of the leaflets from the ventricular side to create leaflet apposition. Once leaflet insertion is confirmed by echocardiography, the clip can be released. If a suboptimal grasp occurs, the leaflet can be released, allowing repositioning before a second grasp attempt. These patients were almost a decade older (mean age, 67 years) than in usual surgical series and had more comorbidities. Major adverse events at 30 days were significantly less frequent with MitraClip therapy (9. In patients with acute 41 MitraClip therapy success, the result appears durable, with a very low rate of later mitral valve surgery. MitraClip for severe symptomatic mitral regurgitation in patients at high surgical risk. Several other devices, designed to provide leaflet repair, including NeoChord, Mitra-Spacer, and MitraFlex, are in preclinical or phase 1 evaluation (see Table 72. The goal of this approach is to remodel the posterior annulus, cinching the great cardiac vein or pushing on the posterior annulus from the vein to improve leaflet coaptation. Treatment of functional mitral valve regurgitation with a percutaneous annuloplasty system. The limited efficacy is related to the location of the coronary sinus relative to the annulus (up to 10 mm more cranial), great individual anatomic variability, and limited benefit of partial annular remodeling. Some “super-responders” may be identified on the basis of anatomic considerations before the procedure. In addition to the risk for damage to the cardiac venous system, devices in this location can compress the left circumflex or diagonal coronary arteries, which traverse between the coronary sinus 43 and the mitral annulus in most patients. In this regard, one novel indirect approach to reduce the septal-lateral dimension that deserves further consideration is the cerclage annuloplasty technique, which recently entered clinical evaluation. This approach attempts to create a more complete circumferential annuloplasty by placing a suture from the coronary sinus through a septal perforator vein into the right atrium or ventricle, where it is snared and 44 tensioned with the proximal end from the right atrium to create a closed pursestring suture. Direct Annuloplasty and Left Ventricular Remodeling Techniques Several devices have been developed to remodel more directly the mitral annulus, in part because of the limitations of indirect coronary sinus annuloplasty described earlier (see Table 72. In this procedure a transaortic catheter is advanced to the left ventricle and used to deliver pledgeted anchors through the posterior annulus that can be pulled together to shorten (plicate) the annulus up to 17 mm (with two implants) (Fig. The Accucinch (Guided Delivery Systems) device utilizes a catheter approach to place up to 12 anchors along the ventricular surface of the posterior mitral annulus. A cable running through the anchors is tensioned to create posterior annular plication. In a later development the anchors are placed in the ventricular myocardium just below the valve plane (percutaneous ventriculoplasty). This is an adjustable, catheter-delivered, sutureless device that is inserted transseptally and directly anchored on the atrial side of the annulus with subsequent adjustment (Fig. Preclinical work with a transcatheter approach to approximate the papillary muscles is also in development (Tendyne Repair).

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In some indi- viduals who take very large doses of arsenic purchase cheap avanafil on line smoking erectile dysfunction statistics, death may be so rapid that there is no chance to develop gastrointestinal symptoms purchase avanafil visa erectile dysfunction from diabetes. Rather generic avanafil 100 mg with mastercard erectile dysfunction ugly wife, the individual becomes comatose, develops convulsions, and dies within several hours. Cyanide The second drug that comes to mind when one talks about homicidal poi- soning is cyanide. Cyanide has been discussed in detail in another section of the book and this discussion will not be repeated. Strychnine Strychnine is a powerful alkaloid found in the seeds of Strychnos nux-vomica. Strychnine was used in the early part of the 20th century medicinally, but, at present, is mostly used as an animal poison. It is rapidly absorbed from the stomach, with symptoms occurring within a few minutes. Because of this, the use of strychnine 532 Forensic Pathology as a homicidal agent is difficult and it is better suited for suicide. There are violent convulsions with opisthotonos, whereby the body rests only on the heels and head. If the individual survives, the convulsions will generally disappear within 12–24 h. Lethal levels of strychnine in adults who die within 1 h of ingestion have ranged from 5 to 90 mg/L. In the older forensic literature, these were three drugs that could be used to commit murder, with a fair certainty that they could not be detected. Digoxin is a cardiac glycoside used in the treatment of congestive heart failure and other cardiac disorders. On an empty stomach, the maximum serum concentration is reached approximately 1 h after oral inges- tion. Because of this, the authors recommend that any analysis of digoxin be done on the vitreous. In the cases the authors have seen in which death was caused by an overdose of digoxin, levels in the vitreous have generally been 10 ug/L and above. Victims of homicidal poi- soning have generally been the elderly or young children. Analysis for digoxin is now extremely simple, and is performed on a routine basis in virtually all hospitals by immunoassay. Succinylcholine is a neuromuscular blocking agent first synthesized in 1906, though its properties as a blocking agent were not recognized until 1949. Unlike D-tubocurarine, which combines with the cholinergic receptor sites blocking competitively the transmitter action of acetylcholine, succinyl- choline is a depolarizing agent. This depolarization is longer lasting, however, and results in repetitive excitation, which may be seen as transient muscular fasciculation. This, in turn, is followed by a phase of blocking of transmission with neu- romuscular paralysis. Following intravenous injection of succinylcholine, there is a brief period of muscular fasciculation, followed by complete paral- ysis that disappears usually within 5 min. During this time, though there is Interpretive Toxicology: Drug Abuse and Drug Deaths 533 complete paralysis of the musculature, the individual is completely conscious. If the individual is not maintained on a respirator, he will die of anoxia due to an inability to breathe. Succinylcholine is rapidly hydrolyzed by plasma cholinesterase and liver esterases to succinylmonocholine and then succinic acid and choline. Prior to the early 1980s, there was no valid method of analysis for succi- nylcholine in tissues. The authors have seen a number of cases of suicide from succinylcholine, usually involving med- ical personnel, and one case of documented homicide. The latter case involved a 15-month-old girl injected in the thigh with succiny1choline by a nurse. The internal viscera were returned to the body cavity and the body was embalmed and buried. Muscle from both thighs, the kidneys, and a portion of liver were retained for toxicological purposes. On analysis, succinylcholine was dem- onstrated in the musculature of both thighs, as well as in the liver and kidneys. Until the introduction of radioimmunoassay, death caused by insulin was extremely difficult to prove. An overdose of insulin will cause hypoglycemia with irreversible injury to the brain. The homicide involved a 43-year-old nondiabetic male who was found dead in bed by his wife. She summoned the police and told them he had been hospitalized for bleeding caused by liver disease, but refused to stay in the hospital. A physician at one of the hospitals he had been seen at was contacted and agreed to sign the death certificate. Relatives of the deceased contacted the medical examiner’s office and stated that he had been separated from his wife and had just gone to visit her. The body was transported to the medical examiner’s office, where a complete autopsy was performed. In spite of the arterial embalming, a large quantity of blood mixed with embalming fluid was still present in the heart and aorta. They showed an interesting pattern of multiple hospital and emergency room 534 Forensic Pathology admissions over a 1-year period for severe hypoglycernia. At the time of all of these inci- dents, the deceased had apparently been drinking and had been “found” unconscious or seizing by his wife. Because of this history, insulin levels were performed on the blood obtained at autopsy in spite of the fact that it had been contaminated with embalming fluid. Subsequent investigation disclosed that the patient’s wife was diabetic and on insulin. The cause and manner of this death were certified as acute insulin overdose, homicide. Insulin is produced in the beta cells of the islets of Langerhans by the enzymatic cleavage of the precursor polypeptide proinsulin. For every mol- ecule of insulin formed, a corresponding molecule of C-peptide is formed. Classically, diabetes has been treated by the administration of insulin obtained either from cattle or swine.

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The bevel of the scope is then used to advance through the cricopharyngeal muscle (upper esophageal sphincter) with an upward lifting movement discount 200 mg avanafil erectile dysfunction treatment karachi, entering the cervical esophagus purchase avanafil 50 mg line impotence blood circulation. As the scope advances discount 100mg avanafil otc erectile dysfunction treatment germany, the head may have to be lowered or the neck extended and the scope directed slightly toward the left. The scope is advanced to the gastroesophageal junction with great care to ensure a visible lumen is seen at all times to avoid inadvertent perforation. Flexible fiberoptic esophagoscopy is performed in an essentially identical manner. Biopsies may be taken and percutaneous gastrostomy tubes may be placed using the fiberoptic esophagoscope. It is usually performed as part of the evaluation of patients with newly diagnosed cancer of the head and neck for several reasons: (a) to gauge the extent of the primary tumor and to evaluate resectability; (b) to evaluate for the presence of synchronous tumors in other locations within the upper aerodigestive tract; and (c) to identify the source of the primary lesion in patients who present with secondary cervical metastases. Identification of the source of the primary lesion allows for more directed therapy, tailored irradiation fields, improved local control, and decreased morbidity. Patient fluid and nutritional status may be further compromised by preexisting malignancy. Meticulous attention to airway management is paramount in these procedures, and close communication with the surgeon is essential. Some patients presenting for esophagoscopy may have obstructing lesions of the esophagus or Zenker’s diverticulum, active gastrointestinal bleeding, or require the removal of a foreign body, putting them at increased risk of aspiration. Airway management requires careful planning and continuous communication with the surgeon. Surgical requirements include adequate muscle relaxation (movement, coughing, or bucking during endoscopy may have disastrous consequences) and immobile vocal cords for vocal cord surgery. Adequate depth of anesthesia is essential, but the requirements for rapid awakening and return of laryngeal reflexes present additional challenges in anesthetic management. As an alternative, in selected patients, flexible bronchoscopy can be performed without tracheal intubation through the Patil-Syracuse mask during manual bag-mask ventilation. Placement and manipulation of the flexible bronchoscope by the surgeon will be facilitated by the concomitant use of one of the hollow oral airways used for the fiberoptic intubation (e. Flexible esophagoscopy is rarely performed as an isolated procedure but, if done, would also be facilitated by tracheal placement of a small-diameter (e. Following muscle relaxation,2 the surgeon may proceed, without securing an airway. After the rigid bronchoscope is introduced into the patient’s trachea, it is connected to an anesthesia circuit through a flexible side port adapter (Racine, Fig. Close communication with the surgeon is essential for adjusting ventilation when the bronchoscope is introduced into the mainstem bronchus to avoid high inflating pressures and to ensure complete exhalation (↓ risk of barotrauma). A n intermittent apnea technique involves hyperventilation, followed by intermittent tracheal extubation for 1–5 min, during which the laser is used. This approach is time consuming and may be associated with a higher incidence of airway trauma and edema 2° repeated intubations. For supraglottic manual jet ventilation, the ventilating laryngoscope is most commonly employed. The axis of the jet should be in line with the trachea, and full egress of air (complete chest deflation) should be ensured between the jet ventilator “puffs. The jet should be triggered during pauses between laser firings to keep the vocal cords immobile. Jet ventilation generally provides adequate ventilation without introducing flammable material into the airway or obstructing the surgical field. Its use, however, may be associated with potentially severe complications, including barotrauma, pneumothorax and gastric distension (risk of regurgitation), and is hindered by ↓ chest-wall into the airway or lung compliance. The oxygen supply at 50 psi is connected to a reducing valve that allows the pressure to be adjusted from 0 to 50 psi. The side port of the endoscope is used as the Venturi injector site, and the open end can be used for continuous viewing by the endoscopist. Bacher A, Lang T, Weber J, et al: Respiratory efficacy of subglottic low- frequency, subglottic combined-frequency, and supraglottic combined-frequency jet ventilation during microlaryngeal surgery. Donati F, Meistelman C, Benoit P: Vecuronium neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis. Jaquet Y, Monnier P, Van Melle G, et al: Complications of different ventilation strategies in endoscopic laryngeal surgery: a 10-year review. It is wise to convert this to a tracheostomy as soon as it is convenient to do so as this reduces the subsequent incidence of subglottic stenosis and cricoid chondritis. A tracheotomy is generally done in a controlled setting, either under general anesthesia in an intubated patient or under local anesthesia. Either a short transverse incision 1–2 cm inferior to the cricoid or a midline vertical incision beginning at the same location may be used. Strap muscles are retracted laterally, the thyroid isthmus is divided if necessary, and in adults an inferiorly based tracheal flap consisting of the 2nd or 3rd tracheal ring is made and secured to the skin inferiorly. In small children, it is better to make only a vertical midline incision to minimize the incidence of stenosis; left and right stay sutures are then placed to assist in reintubation in the event of accidental dislodgment of the tracheotomy tube. Trach ties supplement this securing of the tube unless these circumferential ties would interfere with venous drainage of a flap used in the head and neck reconstruction. When prolonged use of a tracheotomy is anticipated and it is unlikely that mechanical ventilation will be needed, there are specialized silicon tracheotomy tubes with minimal intraluminal plastic and may be associated with fewer intraluminal potential complications. Usual preoperative diagnosis: Indications for tracheostomy are numerous, but share the common theme of securing a safe airway either in anticipation of postop airway edema, inability to protect the airway from aspiration, or as an urgent need to obtain an upper airway in pending obstruction. The fastest way to obtain an airway in an outright emergency when intubation is not an option is a cricothyrostomy. Rarer indications are bilateral vocal cord paralysis or a history of recurrent allergy associated with larynogspasm. If the latter constitutes life- threatening emergency, tracheotomy/cricothyroidotomy may be the preferred approach. Aside from an occasional otherwise healthy patient in the 3rd category, all patients presenting for tracheostomy are usually debilitated, have associated cardiac or pulmonary disease, and frequently present with neurological and metabolic abnormalities. In the presence of significant airway compromise or anticipated very difficult intubation local anesthesia may be required. Mcguire G, El-Beheiry H, Brown D: Loss of the airway during tracheostomy: rescue oxygenation and re-establishment of the airway. It also can be caused by β-hemolytic streptococci, staphylococci, pneumococci, or unusual pathogens among immunocompromised individuals and drug/alcohol abusers. At one time, the typical patient was a previously healthy child 3–5 yr old; however, since the advent of the H-flu vaccine, epiglottitis is more common in adults (predominantly males). The most common presenting symptoms are sore throat, dysphagia/odynophagia, fever, respiratory difficulty, and drooling. Patients presenting with imminent or actual airway obstruction should be intubated immediately.

Magnesium replacement should be administered for signs or symptoms of hypomagnesemia (arrhythmias buy 100mg avanafil free shipping what age can erectile dysfunction occur, muscle cramps) and can be routinely given (with + uncertain benefit) to all patients receiving large doses of diuretics or requiring large amounts of K replacement cheap generic avanafil uk erectile dysfunction medication with high blood pressure. The modest hyperglycemia or hyperlipidemia produced by thiazide diuretics is not usually clinically important cheap avanafil 200mg visa erectile dysfunction 16 years old, and blood glucose and lipids are usually easily controlled using standard-practice guidelines. Hypotension and Azotemia The excessive use of diuretics can lead to a decreased blood pressure, decreased exercise tolerance, and increased fatigue, as well as impaired renal function. Hypotensive symptoms usually resolve after a decrease in the dose or frequency of diuretics in patients who are volume depleted. In most patients, however, use of diuretics is associated with decreased blood pressure and mild azotemia, which do not lead to patient symptoms. In these cases, reductions in the diuretic dose are not necessary, particularly if the patient remains edematous. Ototoxicity Ototoxicity, which is more frequent with ethacrynic acid than the other loop diuretics, can manifest as tinnitus, hearing impairment, and deafness. Diuretic Resistance One of the inherent limitations of diuretics is that they achieve water loss through excretion of solute at the expense of glomerular filtration, which in turn activates a set of homeostatic mechanisms that ultimately limit their effectiveness. In normal patients the magnitude of natriuresis following a given dose of diuretic declines over time as a result of the “braking phenomenon” (Fig. This rightward shift has been referred to as “diuretic resistance” and is likely caused by several factors in addition to the braking phenomenon. Bars represent 6-hour periods before (in Na balance) and after doses of loop diuretic (D). The solid red portion of the open bars indicates the amount by which Na excretion exceeds intake during natriuresis. The hatched areas indicate the amount of positive Na balance after the diuretic effect has worn off. Net Na balance during 24 hours is the difference between the shaded area below the stippled line (postdiuretic NaCl retention) and the solid areas within the bars (diuretic-induced natriuresis). Chronic adaptation is indicated by progressively smaller peak natriuretic effects (the braking phenomenon) and is mirrored by a return to neutral balance. Note that steady state is reached within 6 to 8 days despite continued diuretic administration. Accordingly, after a period of natriuresis, the diuretic concentration in plasma and tubular fluid declines below the diuretic + threshold. In this situation, renal Na reabsorption is no longer inhibited, and a period of antinatriuresis or postdiuretic NaCl retention ensues. This observation forms the rationale for administering short-acting diuretics several times per day to obtain consistent daily salt and water loss. Third, diuretics increase solute delivery to distal segments of the nephron, causing epithelial cells to undergo both hypertrophy and hyperplasia. Moreover, studies in healthy men have shown that pioglitazone stimulates plasma renin activity, which may + contribute to increased Na retention. Rarely, drugs such as probenecid or high plasma concentrations of some antibiotics may compete with the organic ion transporters in the proximal tubule responsible for the transfer of most diuretics from the recirculation into the tubular lumen. The use of increasing doses of vasodilators, with or without a marked decline in intravascular volume as a result of concomitant diuretic therapy, may lower renal perfusion pressure below that necessary to maintain normal autoregulation and glomerular filtration in patients with renal artery stenosis from atherosclerotic disease. Therefore, a reduction in renal blood flow may occur despite an increase in cardiac output, thereby leading to a decrease in diuretic effectiveness. In outpatients, a common and useful method for treating the diuretic-resistant patient is to administer two classes of diuretic concurrently. Adding a proximal tubule diuretic or a distal collecting tubule diuretic to a regimen of loop diuretics is often dramatically effective. As a general rule, when adding a second class of diuretic, the dose of loop diuretic should not be altered because the shape of the dose-response curve for loop diuretics is not affected by the addition of other diuretics, and the loop diuretic must be given at an effective dose for it to be effective. The combination of loop and distal collecting tubule diuretics has been shown to be effective 25 through several mechanisms. One is that distal collecting tubule diuretics have longer half-lives than loop diuretics and may thus prevent or attenuate postdiuretic NaCl retention. A second mechanism by + which distal collecting tubule diuretics potentiate the effects of loop diuretics is by inhibiting Na transport along the proximal tubule, since most thiazide diuretics also inhibit carbonic anhydrase, as well as by inhibiting NaCl transport along the distal renal tubule, which may counteract the increased solute resorptive effects of the hypertrophied and hyperplastic distal epithelial cells. The selection of distal collecting tubule diuretic to use as second diuretic is a matter of choice. Distal collecting tubule diuretics may be added in full doses (50 to 100 mg/day hydrochlorothiazide or 2. However, such an approach is likely to lead to excessive fluid and electrolyte depletion if patients are not followed extremely closely. One reasonable approach to combination therapy is to achieve control of fluid overload by initially adding full doses of distal collecting tubule diuretic on a daily basis and then decreasing the dose of the distal collecting tubule diuretic to three times weekly to avoid excessive diuresis. This approach requires the use of a constant-infusion pump but permits more precise control of the natriuretic effect achieved over time, particularly in carefully monitored patients. This impairment in renal function often is dismissed as “pre-renal”; however, when measured carefully, neither cardiac output nor renal perfusion pressure have been shown to be reduced in diuretic-treated patients who develop the cardiorenal syndrome. Importantly, worsening indices of renal function contribute to longer 28 hospital stays and predict higher rates of early rehospitalization and death (see Fig. The mechanisms for and treatment of the cardiorenal syndrome remain poorly understood. Device-Based Therapies Mechanical methods of fluid removal may be needed to achieve adequate control of fluid retention, particularly in patients who become resistant and/or refractory to diuretic therapy(see Chapter 24). Alternative extracorporeal methods include continuous hemofiltration, hemodialysis, or hemodiafiltration. The primary endpoint was total weight loss during the first 48 hours of randomization and the change in dyspnea score during the first 48 hours of randomization. In addition to extracorporeal methods for relieving volume overload, peritoneal dialysis can be used as a viable alternative therapy for the short-term management of refractory congestive symptoms for patients in whom vascular access cannot be obtained, or for whom appropriate extracorporeal therapies are not available. Participants treated with enalapril had significantly lower mortality than those treated with the vasodilatory combination of hydralazine plus isosorbide dinitrate (which does not directly inhibit neurohormonal systems). Nonetheless, it should be emphasized that patients with a low blood pressure (<90 mm Hg systolic), or impaired renal function (serum creatinine >2. Thus the efficacy of these agents for this latter patient population is less well established. Potassium retention may also become problematic if the patient is receiving potassium supplements or a potassium-sparing diuretic. The combination of hydralazine and an oral nitrate should be considered for these latter patients (see Table 25. Therefore the problems of symptomatic hypotension, azotemia, and hyperkalemia will be similar for both these agents. However, compliance with this combination has generally been poor because of the large number of tablets required and the high incidence of adverse reactions. A, Death from cardiovascular causes or hospitalization for heart failure (the primary endpoint). There are additional concerns about effects of sacubitril/valsartan on the degradation of beta- amyloid peptide in the brain, which could theoretically accelerate amyloid deposition. Beta blockers interfere with the harmful effects of sustained activation of the central nervous system by competitively antagonizing one or more alpha- and beta-adrenergic receptors (α , β ,1 1 and β ).

By Q. Gelford. Pratt Institute.

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